4.6 Article

Functional characterization of MLH1 missense variants unveils mechanisms of pathogenicity and clarifies role in cancer

期刊

PLOS ONE
卷 17, 期 12, 页码 -

出版社

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0278283

关键词

-

资金

  1. University of Monastir, Tunisia
  2. Higher Institute of Biotechnology of Monastir, Tunisia

向作者/读者索取更多资源

This study identified three MLH1 missense alterations and determined their pathogenicity through laboratory testing. Two of the variants were confirmed to be pathogenic, enabling predictive testing and targeted surveillance in carrier family members.
Lynch syndrome is a heritable condition caused by a heterozygous germline inactivating mutation of the DNA mismatch repair (MMR) genes, most commonly the MLH1 gene. However, one third of the identified alterations are missense variants, for which the clinical significance is unclear in many cases. We have identified three MLH1 missense alterations (p.(Glu736Lys), p.(Pro640Thr) and p.(Leu73Pro)) in six individuals from large Tunisian families. For none of these alterations, a classification of pathogenicity was available, consequently diagnosis, predictive testing and targeted surveillance in affected families was impossible. We therefore performed functional laboratory testing using a system testing stability as well as catalytic activity that includes clinically validated reference variants. Both p.(Leu73Pro) and p.(Pro640Thr) were found to be non-functional due to severe defects in protein stability and catalytic activity. In contrast, p.(Glu736Lys) was comparable to the wildtype protein and therefore considered a neutral substitution. Analysis of residue conservation and of the structural roles of the substituted residues corroborated these findings. In conjunction with the available clinical data, two variants fulfil classification criteria for class 4 likely pathogenic. The findings of this work clarify the mechanism of pathogenicity of two unclear MLH1 variants and enables predictive testing and targeted surveillance in members of carrier families worldwide.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.6
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据